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Autoinflammatory diseases Flashcards

1
Q

What leads to the production of inflammatory cytokines?

A

Infection

Tissue damage

Environmental stress

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2
Q

What differentiates autoimmune from autoinflammatory conditions?

A

They lie on opposite ends of the same spectrum

Result due to opposite mechanisms

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3
Q

What is overactive in autoinflammatory conditions?

A

The innate immune system

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4
Q

What is overactive in autoimmune conditions?

A

The adaptive immune system

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5
Q

What are the different classes of autoinflammatory and autoimmune conditions?

A

Polygenic

Monogenic

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6
Q

What is a polygenic condition?

A

Many genes are responsible for the pathology

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7
Q

What is a monogenic condition?

A

One gene is responsible for the pathology

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8
Q

Examples of rare monogenic autoinflammatory diseases

A

CAPS

FMF

TRAPS

PAPA

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9
Q

Examples of polygenic autoinflammatory diseases

A

Still’s

Chron’s

Ulcerative colitis

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10
Q

Examples of mixed pattern diseases

A

Reactive psoriasis arthritis

Ankylosing spondylitis

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11
Q

Examples of classic polygenic autoimmune diseases

A

Rheumatoid arthritis

SLE

Type 1 diabetes

Sjorgen’s syndrome

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12
Q

What is a central mediator of symptoms and signs in autoinflammatory syndromes?

A

IL-1b

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13
Q

What is the death domain superfamily?

A

Member of the innate immune system

Play pivotal roles in apoptosis and inflammation

Group of highly conserved and closely related proteins

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14
Q

How many death domains are there in the death domain superfamily?

A

39

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15
Q

How many death effector domains are there in the death domain superfamily?

A

8

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16
Q

How many caspase recruitment domains are there in the death domain superfamily?

A

33

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17
Q

How many pyrin domains are there in the death domain superfamily?

A

22

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18
Q

Describe the shape of death domains

A

6 a-helices arranged in antiparallel bundle

Homotypic protein protein interactions

No cross interactions between families

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19
Q

What are the characteristics of autoinflammatory conditions?

A

No class II HLA-association

No gender predisposition

No auto-antibodies

No antigen-specific T cells

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20
Q

How have autoinflammatory diseases been beneficial to the scientific community?

A

Allowed us to understand the mechanisms regulating inflammation

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21
Q

Give an example of an autoinflammatory condition that has helped us understand the mechanisms regulating inflammation

A

CAPS

Shed light on the role of the NLRP3 inflammasome

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22
Q

What are the symptoms of autoinflammatory syndromes?

A

Fever

Serositis

Arthritis

Rash

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23
Q

What are common genetic links in autoinflammatory conditions?

A

Inherited or acquired

Inherited forms usually manifest early

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24
Q

What are the common mechanisms that are faulty in autoinflammatory conditions?

A

Cytokine dysregulation

Abnormal protostasis

ER and mitochondrial stress

Autophagy

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25
What criteria must a patient follow in order to be diagnosed with an inflammatory condition?
Recurrent or continuous symptoms Family history Exclusion of other causes Elevated acute phase response proteins
26
What is CAPS?
Range of conditions caused by the same gene mutation But presents differently Caused by mutations in the NLRP3 on chromosome 1
27
What are the three conditions caused by mutations in the NLRP3 gene?
Familial cold urticaria Muckle Wells Syndrome NOMID/CINCA
28
What is the genetic link of Familial cold urticaria?
Autosomal dominant
29
What is the genetic link of Muckle Wells syndrome?
Autosomal dominant
30
What is the genetic link of NOMID/ CINCA?
Sporadic
31
What are the symptoms of Familial Cold Urticaria?
Cold induced rash Arthralgia Conjunctivitis
32
What are the symptoms of Muckle Wells syndrome?
Sensorineural deafness AA amyloidosis
33
What are the symptoms of NOMID/CINCA?
Progressive chronic meningitis Destructive arthritis
34
What is the severity of Familial cold urticaria?
Mild Only presents in the cold
35
What is the severity of Muckle wells syndrome?
Moderate
36
What is the severity of NOMID/CINCA?
Very severe Sufferers die in childhood
37
What are the day-to-day symptoms of CAPS?
Widespread uritcarial rash Flu-like symptoms Anaemia Headaches Fatigue Depression
38
What are the long-term symptoms of CAPS?
Neurological damage Sensorineural deafness Visual loss Cognitive impairment AA amyloidosis
39
What activates the NLRP3 inflammasome?
Potassium efflux induced by bacterial proteins or extracellular ATP which interacts with K+ channels DAMPs or PAMPs forming phagolysosomal vessels Transcription of proinflammatory cytokines
40
What type of molecule is NLRP3?
NOD
41
What are NODs?
As supposed to TLRs, they are cytosolic receptors
42
Consequences of NLRP3 activation
Amplifies the immune response Causes apoptosis
43
How does NLRP3 detect PAMPs or DAMPs?
Through leucine rich repeats
44
How does the NLRP3 amplify the immune response?
Initiates caspase-1 self-cleavage and forms active caspase-1
45
How does caspase-1 cause the effects on the inflammatory system?
Stimulates cleavage of pro-IL1b into activated IL-1b
46
How do mutations to the NLRP3 cause autoinflammatory conditions?
Leads to constitutive overactivation of caspase 1 Leads to spontaneous formation of the IL-1 inflammasome Continuous production of IL-1b
47
Which targets does IL-1b affect?
Brain Bone Endothelial cells
48
How does IL-1b affect the brain?
On the hypothalamus Induces fever and pain sensitisation
49
How does IL-1b affect bones?
Bone resorption Cartilage breakdown Production and enhanced activation of immune cells Causes the release of inflammatory molecules
50
How does IL-1b affect endothelial cells?
Releases IL-6 Causes the production and release of acute phase response proteins from the liver
51
What is the correlation between IL-1b concentration and CAPS presentation?
The higher the IL-1b concentration in the blood, the more severe the presentation of the disease
52
What are treatments of CAPS?
IL-1 blockade Caspase 1 inhibition IL-1b receptor blockade
53
What was the result of IL-1 blockade as a treatment for CAPS?
Reduced levels of IL-1b Without decreasing it too much below physiological levels
54
What was the result of caspase 1 inhibition?
Lowering IL-1b concentration was made possible, but a high amount needed to make a small change Caspase-1 is important in other processes Moderately reduced serum cytokine concentration
55
What is Anakinra?
A drug used for CAPS that blocks the IL-1 receptor Prevents IL-1b from binding And so prevents IL-1 from working intracellulary
56
What is the half-life of Anakinra?
4-6 hours
57
What was the effect of Anakinra in CAPS patients?
Affected individuals developed normal kidney function and went from infertile to fertile because of the drug
58
Where is Anakinra derived from?
Recombinant form of endogenous IL-1Ra
59
What were the limitations of Anakinra?
Difficult to obtain funding for the expensive drug Daily sometimes painful injections required Injection site reactions Inconvenient - needs to be stored between 2-8 degrees, repeated dosing within 24 hr is crucial Major rebound flares Infectious risks
60
What are the advantages of Anakinra?
Short half-life meant it was safe since it was cleared out in the urine within a few hours CAPS sufferers were sensitive to IL-1 receptor blockade when all other therapies were unsuccessful
61
Why was CAPS a good disease to test novel therapies?
IL-1 was thought to play a major role in many acquired diseases CAPS is a disease with very clear parameters
62
Why is CAPS a condition with clear parameters?
Patients have defined, clear symptoms There is a genetic test for the condition Blood test results correlated with the level of disease in the patient
63
What was found to be a good alternative drug to Anakinra?
Canakinumab
64
Why was Canakinumab a better alternative than Anakinra?
Fully human IgG cap antibody targeted against IL-1b Showed rapid improvement of symptoms within hours Levels of biomarkers lowered to normal and maintained for 115 days after one dose
65
What is the safety profile of Canakinumab?
Well-tolerated Few infection-site reactions No evidence for development of antibodies or immunogenicity
66
What conditions are similar to CAPS?
Familial Mediterranean Fever TRAPS DIRA DITRA MKD
67
What is FMF?
Familial Mediterranean Fever Commonest genetic disease in the East Mediterranean
68
What are the symptoms of FMF?
Recurrent, self-limiting episodes of fever, peritonitic pain, pleurtic pain and arthritis Lasts 48-72 hours
69
What gene defect leads to FMF?
Mutation in the MEFV gene
70
How does the mutation of MEFV lead to FMF?
MEFV gene codes for the pyrin protein This is a gain of function mutation Causes overactivation of caspase-1 and more IL-1b to become released
71
Do FMF patients have increased or decreased chances of developing infections?
Decreased These patients have lower infection rates because of the increased IL-1b release
72
What is pyrin?
A component of the inflammasome
73
What is the function of pyrin?
Activates caspase-1 by autoproteolysis Indirect sensor of many bacterial toxins through their effects on actin
74
What is colchicine?
An effective prophylaxis to FMF Root found naturally
75
Why is colchicine effective in FMF if it has a low therapeutic index?
It concentrates in neutrophils Because they lack the P-glycoprotein efflux pump that removes it from the inside of the cell
76
How does colchicine effectively treat FMF?
Competes with cleaving of NF-kB Decreases the concentration of NFkB in the blood
77
How does colchicine cause effects on the cells it targets?
Binds to tubulin to arrest microtubule polymerization Inhibits neutrophil chemotxis Suppresses NF-kB activation Reduces levels of inflammatory cytokines
78
What is the mortality of FMF patients?
Comparable to normal population AA amyloidosis causes death in the undiagnosed population
79
What are the reproductive outcomes of FMF patients?
Comparable to the normal population Colchicine does not have effects on fertility
80
What are the incidences of colchicine resistance in FMF patients?
Rare IL-1 agents are used in such case

Molecular Basis of Disease (28 decks)

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